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7109003 
Journal Article 
Flufenamic acid as an inducer of mitochondrial permeability transition 
Jordani, MC; Santos, AC; Prado, IMR; Uyemura, SA; Curti, C; , 
2000 
Molecular and Cellular Biochemistry
ISSN: 0300-8177
EISSN: 1573-4919 
KLUWER ACADEMIC PUBL 
DORDRECHT 
210 
1-2 
153-158 
English 
To assess the mechanism by which mitochondrial permeability transition (MPT) is induced by the nonpolar carboxylic acids, we investigated the effects of flufenamic acid (3'-trifluoromethyl diphenylamine-2-carboxylic acid, FA) on mitochondrial respiration, electrical transmembrane potential difference (Delta Psi), osmotic swelling, Ca2+ efflux, NAD(P)H oxidation and reactive oxygen species (ROS) generation. Succinate-energized isolated rat liver mitochondria incubated in the absence or presence of 10 mu M Ca2+, 5 mu M ruthenium red (RR) or 1 mu M cyclosporin A (CsA) were used. The dose response-curves for both respiration release and Delta Psi dissipation were nearly linear, presenting an IC50 of approximately 10 mu M and reaching saturation within 25-50 mu M, indicating that FA causes mitochondrial uncoupling by a protonophoric mechanism. Within this same concentration range FA showed the ability to induce MPT in energized mitochondria incubated with 10 mu M Ca2+, followed by Delta Psi dissipation and Ca2+ efflux, and even in deenergized mitochondria incubated with 0.5 mM Ca2+. ADP, Mg2+, trifluoperazine (TFP) and N-ethylmaleimide (NEM) reduced the extent of FA-promoted swelling in energized mitochondria by approximately one half, whereas dithiothreitol (DTT) slightly enhanced it. NAD(P)H oxidation and ROS generation (H2O2 production) by mitochondria were markedly stimulated by FA; these responses were partly prevented by CsA, suggesting that they may be implicated as both a cause and effect of FA-induced MPT. FA incubated with mitochondria under swelling assay conditions caused a decrease of approximately 40% in the content of protein thiol groups reacting with 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB). The present results are consistent with a ROS-intermediated sensitization of MPT by a direct or indirect FA interaction with inner mitochondrial membrane at a site which is in equilibrium with the NAD(P)H pool, namely thiol groups of integral membrane proteins. 
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     3,3,3-Trifluoro-1-propene